Syringaresinol Reverses Age-Related Skin Atrophy by Suppressing FoxO3a-Mediated Matrix Metalloproteinase–2 Activation in Copper/Zinc Superoxide Dismutase–Deficient Mice

Aging is characterized by accumulation of chronic and irreversible oxidative damage, chronic inflammation, and organ dysfunction. Superoxide dismutase (SOD) serves as a major enzyme for cellular superoxide radical metabolism and physiologically regulates cellular redox balance throughout the body. Copper/zinc superoxide dismutase–deficient (SOD1 ^–/– ) mice showed diverse phenotypes associated with enhanced oxidative damage in whole organs. Here, we found that oral treatment with syringaresinol (also known as lirioresinol B), which is the active component in the berries of Korean ginseng (Panax ginseng C.A. Meyer), attenuated the age-related changes in Sod1 ^–/– skin. Interestingly, syringaresinol morphologically normalized skin atrophy in Sod1 ^–/– mice and promoted fibroblast outgrowth from Sod1 ^–/– skin in vitro. These protective effects were mediated by the suppression of matrix metalloproteinase-2 overproduction in Sod1 ^–/– skin, but not by increased collagen expression. Syringaresinol also decreased the oxidative damage and the phosphorylation of FoxO3a protein, which was a transcriptional factor of matrix metalloproteinase–2, in Sod1 ^–/– skin. These results strongly suggest that syringaresinol regulates the FoxO3–matrix metalloproteinase-2 axis in oxidative damaged skin and exhibits beneficial effects on age-related skin involution in Sod1 ^–/– mice.